title: Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron syndrome influenced by oxidative stress. The transcription factor Nrf2 and its repressor Keap1 constitute an important defence system in cellular protection against oxidative stress. Here we hypothesize that common genetic variations in the genes NFE2L2 and KEAP1, encoding Nrf2 and Keap1, may influence the risk and phenotype of ALS. Five hundred and twenty-two Swedish patients with sporadic ALS (SALS) and 564 Swedish control subjects were studied. Eight tag SNPs in NFE2L2 and three tag SNPs in KEAP1 were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. One NFE2L2 haplotype (GGGAC) was associated with decreased risk of SALS (OR = 0.62 per allele, p = 0.003) and one haplotype in KEAP1 (CGG) was associated with later SALS onset (+3.4 years per allele, p = 0.015). When stratified by subgroup, one haplotype in NFE2L2, GAGCAGA including three functional promoter SNPs associated with high Nrf2 protein expression, was associated with 4.0 years later disease onset per allele in subgroup ALS (p = 0.008). In conclusion, these results suggest that variations in NFE2L2 and KEAP1, encoding two central proteins in cellular oxidative stress defence, may influence SALS pathogenesis.
authors.affiliation: Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg , Gothenburg , Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Bergström
authors.forename: Malin
authors.initials: M
authors.lastname: von Otter
authors.forename: Staffan
authors.initials: S
authors.lastname: Nilsson
authors.forename: Ann-Charloth
authors.initials: AC
authors.lastname: Nilsson
authors.forename: Michael
authors.initials: M
authors.lastname: Nilsson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Ola
authors.initials: O
authors.lastname: Hammarsten
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D010244:Bulbar Palsy, Progressive / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013548:Sweden
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human